RuO4-Catalyzed Ketohydroxylation of Olefins Bernd Plietker* Organic Chemistry II, Chemistry Faculty, Dortmund University, Otto-Hahn-Str. 6, D-44221 Dortmund, Germany
[email protected] Received June 20, 2003
Abstract: A new mild method for the oxidation of a variety of olefins to R-hydroxy ketones is described. Using the concept of a nucleophilic reoxidant, different olefins were ketohydroxylated with high regioselectivity in good to excellent yields.
Alkenes are useful starting materials for a variety of transformations in organic synthesis.1 The formation of olefins with both defined stereochemistry and substitution pattern can be achieved by the classical olefination of carbonyl compounds or by metal-catalyzed crosscoupling2 or metathesis reactions3 established over the past few years. Further elaborations often imply the addition of heteroatoms across the π-bond. Among these, oxidation reactions belong to the most important transformations. The most likely pericyclic nature of the stereoinducing step in both asymmetric dihydroxylation4 and epoxidation5 is responsible for a direct translation of the π-bond geometry to the relative stereochemistry of the newly formed chiral centers. Despite the great success of these two oxidation reactions it is surprising to find that the direct oxidation of double bonds to R-hydroxy ketones has rarely been investigated.6 Development of RuO4-Catalyzed Ketohydroxylation. Highly oxidized transition metals are the focus of our current research. RuO4 (I) is isoelectronic to OsO4, and hence, during the course of the reaction with olefins, ruthenate esters III and V are formed.7 A concomitant hydrolysis (i.e., the nucleophilic attack of water at the * Corresponding author. (1) Houben-Weyl: Stereoselective Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme-Verlag: Stuttgart, New York, 1996; Vols. 4-9. (2) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, Weinheim, 1998. (3) (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. (b) Fu¨rstner, A. Adv. Synth. Catal. 2002, 344, 567. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Schrock, R. R. In Topics in Organometallic Chemistry 1-Alkene Metathesis in Organic Synthesis; Fu¨rstner, A., Ed.; Springer-Verlag: Berlin, Heidelberg, 1998; p 1. (e) Fu¨rstner, A. In Topics in Organometallic Chemistry 1-Alkene Metathesis in Organic Synthesis; Fu¨rstner, A., Ed.; Springer-Verlag: Berlin, Heidelberg, 1998; p 37. (f). Nicolaou, K. C.; King, N. P.; He, Y. In Topics in Organometallic Chemistry 1-Alkene Metathesis in Organic Synthesis; Fu¨rstner, A., Ed.; Springer-Verlag: Berlin, Heidelberg, 1998; p 73. (4) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, Weinheim, 2000; p 357. (b) Bolm, C.; Hildebrand, J. P.; Muniz, K. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, Weinheim, 2000; p 399. (5) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, Weinheim, 2000; p 231. (b) Katsuki, T. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, Weinheim, 2000; p 287.
FIGURE 1. Proposed mechanism of Ru-catalyzed ketohydroxylation.
metal center) of these cyclic esters leads to syn-diols. We envisioned these compounds to be more than just reactive intermediates. Our working model is based upon the idea to use a reagent capable of functioning as both a nucleophile and reoxidant (Figure 1). It could open a new mechanistic pathway leading to R-hydroxy-ketones VI. The reaction would combine the advantages of the [2 + 3]-cycloaddition (stereoinducing step) of I toward an olefin II and, after the nucleophilic addition, of the intrinsic peroxide substructure in metallo ester V (Figure 1). Since the stereocenter in V has already been established, the oxidative fragmentation should not corrupt the stereochemical outcome of the reaction. However, the mechanism of the fragmentation remains unclear. Apart from a β-hydride elimination pathway from V and subsequent reaction of the resulting Ru-H species with the liberated acyloin anion, an internal deprotonation of the carbinol carbon by the alkoxide substructure could lead to the formation of I, SO42- and ketol VI. Different reoxidants that would match our criteria of a “nucleophilic reoxidant” have been investigated. Some representative results are listed in Table 1. Neither of the common oxidation systems gave significant conversion or high chemoselectivity. However, Oxone under strictly buffered conditions turned out to be the reoxidant of choice (Table 1). The combination of Oxone and RuCl3 in the presence of NaHCO3 (5 equiv) has been used for the oxidative cleavage of double bonds.8,9 To force the reaction into our desired direction we increased the amount of Oxone to 5 equiv in combination with a decrease in the amount of water. Thus, we suppressed a competing hydrolysis of the ruthenate ester and favored the postulated nucleophilic addition of SO52-. A dramatic influence of base on (6) (a) Murahashi, S.-I.; Komiya, N. In Biomimetic Oxidations Catalyzed by Transition Metal Complexes; Meunier, B., Ed.; Imperial College Press: London, 2000; p 563. (b) Murahashi, S.-I. Pure Appl. Chem. 1992, 64, 403. (c) Murahashi, S.-I.; Saito, T.; Hanaoka, H.; Murakami, Y.; Naota, T.; Kumobayashi, H.; Akutagawa, S. J. Org. Chem. 1993, 58, 2929. (d) Murahashi, S.-I.; Naota, T.; Hanaoka, H. Chem. Lett. 1993, 1767. (e) Takai, T.; Yamada, T.; Mukaiyama, T. Chem. Lett. 1991, 1499. (f) Baskaran, S.; Das, J.; Chandrasekaran, S. J. Org. Chem. 1989, 54, 5182. (g) Srinivasan, N. S.; Lee, D. G. Synthesis 1979, 520. (7) Albarella, L.; Lasalvia, M.; Piccialli, V. Sica, D. J. Chem. Soc., Perkin Trans. 2 1998, 737. (8) Yang, D.; Zhang, C.; J. Org. Chem. 2001, 66, 4814. (9) Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824.
10.1021/jo034864p CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/09/2003
J. Org. Chem. 2003, 68, 7123-7125
7123
TABLE 1. Development of the Ketohydroxylation; Part
TABLE 3. Ketohydroxylation of Olefins
I, Influence of Reoxidant
reoxidanta
time
conversion [%]b
2 [%]c
3 [%]c
4 [%]c
t-BuOOH, Et4NOH H2O2, Et4NOH NaOCl Oxone, NaHCO3d
1d 1d 60 min 10 min
30 12 60 80
17 nd 15 66
5 nd 10 23
78 nd 75 11
a All reactions were performed on a 2 mmol scale in a solvent mixture of ethyl acetate (12 mL)/acetonitrile (12 mL)/water (2 mL) at room temperature using 1 mol % RuCl3 (as a 0.1 M stock solution in water) and 5 equiv of reoxidant. b Determined by GC integration. c Percentage refers to the amount of product in the mixture. d 1.5 equiv of NaHCO3 was used.
TABLE 2. Development of the Ketohydroxylation; Part II, Influence of Base Concentration NaHCO3a [equiv]
time [min]
conversion [%]b
2 [%]c
3 [%]c
4 [%]c
1 2.5 5
30 10 60
38 96 86
62 98 21
5 0 6
33 2 73
a All reactions were performed under the conditions listed in Table 1 employing 5 equiv of Oxone. b Determined by GC integration. c Percentage refers to the amount of product in the mixture.
the course of the reaction was observed. When we increased the amount of NaHCO3, the oxidative cleavage is strongly favored (Table 2); different reasons could account for this finding. The NaHCO3 could function as a buffer, thus maintaining the pH throughout the reaction slightly acidic. UV-spectroscopic analysis proved the formation of RuO4 under the given reaction conditions. However, the identification of the catalytically active species and the influence of the pH on the course of the reaction awaits further investigations. With the optimum conditions in hand we were able to selectively ketohydroxylate trans-stilbene 1 to ketol 2 in 94% isolated yield. Scope and Limitations. We turned our attention toward an intense screening of scope and limitations. We were pleased to find that a variety of olefins are ketohydroxylated in high yields and high regioselectivity. Scission products or syn-diols are formed in minor amounts (less than 10%) and can easily be removed by column chromatography. Moreover, the formation of these side products can be further reduced by variation of the amount of water and base. Although the reaction medium is slightly acidic, esters are not hydrolyzed. Furthermore, the reaction times for the full conversion of trans-olefin 1 and the corresponding cis-isomer 5 into ketol 2 were the same, indicating that in contrast to the osmylation reactions the RuO4-catalyzed [2 + 3]-cycloaddition is very fast independent of the olefin geometry. In general electron-rich substrates are ketohydroxylated much faster than electron-poor starting materials. The results are summarized in Table 3. With respect to a future development of an asymmetric version it is important to note that enantiopure ketol 2 did not epimerize under the reaction conditions. The enantiomeric excess was checked before and after 12 h 7124 J. Org. Chem., Vol. 68, No. 18, 2003
a All reaction were performed under the conditions listed in Table 1 employing 5 equiv of Oxone and 2.5 equiv of NaHCO3. b Isolated yield.
of stirring at room temperature, and no decrease in the enantiomeric excess was observed. The results of these experiments and a detailed investigation regarding the reaction scope, functional group tolerance, and diastereoselectivity will be published separately soon. The high regioselectivity in the oxidation of nonsymmetrical olefins is remarkable. We were not able to detect any regioisomeric products from the crude mixture. Different explanations can be used to rationalize the regiochemistry; however, the mechanism remains unclear at this point of our research and awaits further investigation. Apart from the one-step mechanism involving a nucleophilic addition of SO52- to the metal center (Figure 1) an alternative mechanistic scenario could involve a two-step process of syn-dihydroxylation and concomitant mono oxidation of the resulting diol. To get a first insight into the mechanism and the role of our reoxidant, we performed two separate control experiments in which trans-stilbene (1) and hydrobenzoin (3) were treated with RuO4 under the reaction conditions mentioned above (Scheme 1).
FIGURE 2. Conversion-time graph for oxidation of 1 (path A) and 3 (path B).
SCHEME 1. Oxidation of Hydrobenzoin 3 and trans-Stilbene 1
If the overall oxidation occurs in two steps, the reaction of hydrobenzoin (3) as part of the process should be faster than the transformation of trans-stilbene (1). This option can be ruled out, because the ketohydroxylation of 1 is significantly faster than the mono oxidation of 3. In summary, we developed a new direct and mild ketohydroxylation of olefins under Ru(VIII)-catalysis. First results indicate that the products are obtained in one step without formation of an intermediate syn-diol. A variety of olefins can be oxidized regioselectively to R-hydroxy-ketones in good to excellent yields. Further investigation on the scope and limitations, the diastereoselectivity, and the mechanism awaits further investigations. On the basis of these results the development of an asymmetric version should be possible. Experimental Section General Remarks. Petroleum ether refers to that fraction boiling in the range 35-60 °C. HPLC-grade acetonitrile was purchased commercially, and ethyl acetate was purified by distillation over CaCl2 prior to use. RuCl3 was obtained commercially . A stock solution was prepared calculating with RuCl3(H2O)2 and dissolving the catalyst (2.44 g, 10 mmol) in 100 mL of water (0.1 M). The deep brown solution can be stored on the bench for weeks without loss of activity. Literature-known compounds 2,10 7,6g 9,11 11,12 15,13 17,14 and 1915 were characterized by 1H NMR, 13C NMR, and IR spectroscopic data and comparison of these data with the literature reports. (10) Ueyama, N.; Kamabuchi, K.; Nakamura, A. J. Chem. Soc., Dalton Trans. 1985, 635.
General Procedure for Ketohydroxylation. A 100-mL round-bottomed flask equipped with magnetic stirring bar and overpressure valve was charged with NaHCO3 (420 mg, 5 mmol). A 0.1 M aqueous solution of RuCl3 (200 µL, 0.02 mmol) was added, and the suspension was diluted with 2 mL of H2O, 12 mL of CH3CN, and 12 mL of ethyl acetate. Oxone (6.1 g, 10 mmol) was added in one portion to the resulting brownish suspension (gas evolution). When the color turned bright yellow, the olefin (2 mmol) was added in one portion. The reaction was followed by TLC. After complete conversion the mixture was poured onto 30 mL of saturated NaHCO3 and 30 mL of saturated Na2SO3 solution. Phases were separated, and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). After drying of the combined organic layer over Na2SO4 and evaporation of the solvent in a vacuum, the oily crude product was purified by flash chromatography. 2-Hydroxy-1-phenyl-3-(phenylsulfonyl)propan-1-one (13). Yellow solid; mp 78 °C; Rf (pentane/ethyl acetate (5:1)) 0.59; 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, 4H), 6.56-7.67 (m, 6H), 5.60 (dd, J ) 9.7, 1.6 Hz, 1H), 3.57 (dd, J ) 14.8, 1.6 Hz, 1H), 3.29 (dd, J ) 14.8, 9.7 Hz, 1H), 2.95 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 236.3, 197.4, 139.6, 134.9, 134.2, 132.3, 129.4, 129.1, 128.5, 68.7, 61.2; MS (GC-MS) m/z 141 (4) [C6H5SO2], 122 (84), 105 (100) [C6H5CO], 77 (65), 51 (34); IR (KBr) ν 3451 (br), 3064 (m), 1694 (s), 1692 (s), 1310 (s), 1151 (m), 1024 (m), 737 (m); HRMS calcd for [C15H14O4S + H] 291.0691, found 291.0697. Anal. Calcd for C15H14O4S (290.06): C, 62.05; H, 4.86. Found: C, 62.12; H, 4.82. 3-Cyclohexyl-2-hydroxy-3-oxo-propionic Acid Methyl Ester (21). Colorless oil; Rf (pentane/ethyl acetate (3:1)) 0.45; 1H NMR (400 MHz, CDCl ) δ 4.86 (s, 1H), 3.78 (s, 3H), 2.77 (m, 3 1H), 1.61-1.83 (m, 5H), 1.22-1.45 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 207.3, 169.0, 76.3, 53.2, 46.6, 29.3, 27.7, 25.6; MS (GCMS) m/z 201 (71) [M+ + H], 183 (28) [M+ + H - H2O], 83 (71) [C6H11+], 55 (100); IR (film) ν 3448 (br), 2933 (s), 2856 (s), 1749 (s), 1717 (s), 1450 (m), 1242 (m); HRMS calcd for [C10H16O4 + H] 201.1127, found 201.1125. Anal. Calcd for C10H16O4 (200.23): C, 59.98; H, 8.05. Found: C, 59.92; H, 8.11.
Acknowledgment. The author thanks Prof. Dr. N. Krause for generous support and the Fonds der Chemischen Industrie for a Liebig fellowhip. Further financial support by the Deutsche Forschungsgemeinschaft and the Fonds zur Fo¨rderung des wissenschaftlichen Nachwuchses im Fachbereich Chemie der Universita¨t Dortmund is gratefully acknowledged. Supporting Information Available: Text giving detailed experimental procedures, including analytical and spectroscopic data for compounds 2,10 7,6g 9,11 11,12 15,13 17,14 1915. This material is available free of charge via the Internet at http://pubs.acs.org. JO034864P (11) Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. Tetrahedron Lett. 1985, 26, 3837. (12) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1993, 49, 11263. (13) Blatt, K.; Hawkins, W. L. J. Am. Chem. Soc. 1936, 58, 81. (14) Bovicelli, P.; Sanetti, A.; Lupatelli, P. Tetrahedron 1996, 52, 10969. (15) Shing, T. K. M.; Tam, E. K. W.; Tai, V. W. F.; Chung, I. H. F.; Jiang, Q. Chem. Eur. J. 1996, 2, 50.
J. Org. Chem, Vol. 68, No. 18, 2003 7125
